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ACS Infectious Diseases Nov 2021Monocyclic β-lactams with antibiotic activity were first synthesized more than 40 years ago. Extensive early structure-activity relationship (SAR) studies, especially...
Monocyclic β-lactams with antibiotic activity were first synthesized more than 40 years ago. Extensive early structure-activity relationship (SAR) studies, especially in the 1980s, emphasized the need for heteroatom activation of monocyclic β-lactams and led to studies of oxamazins, monobactams, monosulfactams, and monocarbams with various side chains and peripheral substitution that revealed potent activity against select strains of Gram-negative bacteria. Aztreonam, still the only clinically used monobactam, has notable activity against many Gram-negative bacteria but limited activity against some of the most problematic multidrug resistant (MDR) strains of and . Herein, we report that extension of the side chain of aztreonam is tolerated and especially that coupling of the side chain free acid with a bis-catechol siderophore mimetic significantly improves activity against the MDR strains of Gram-negative bacteria that are of most significant concern.
Topics: Anti-Bacterial Agents; Aztreonam; Gram-Negative Bacteria; Microbial Sensitivity Tests; Monobactams; Siderophores
PubMed: 34668698
DOI: 10.1021/acsinfecdis.1c00458 -
The Journal of Antimicrobial... Aug 2022To explore the literature comparing the pharmacokinetic and clinical outcomes from adding probenecid to oral β-lactams. (Meta-Analysis)
Meta-Analysis
OBJECTIVES
To explore the literature comparing the pharmacokinetic and clinical outcomes from adding probenecid to oral β-lactams.
METHODS
Medline and EMBASE were searched from inception to December 2021 for all English language studies comparing the addition of probenecid (intervention) with an oral β-lactam [flucloxacillin, penicillin V, amoxicillin (± clavulanate), cefalexin, cefuroxime axetil] alone (comparator). ROBINS-I and ROB-2 tools were used. Data on antibiotic therapy, infection diagnosis, primary and secondary outcomes relating to pharmacokinetics and clinical outcomes, plus adverse events were extracted and reported descriptively. For a subset of studies comparing treatment failure between probenecid and control groups, meta-analysis was performed.
RESULTS
Overall, 18/295 (6%) screened abstracts were included. Populations, methodology and outcome data were heterogeneous. Common populations included healthy volunteers (9/18; 50%) and those with gonococcal infection (6/18; 33%). Most studies were crossover trials (11/18; 61%) or parallel-arm randomized trials (4/18; 22%). Where pharmacokinetic analyses were performed, addition of probenecid to oral β-lactams increased total AUC (7/7; 100%), Cmax (5/8; 63%) and serum t½ (6/8; 75%). Probenecid improved PTA (2/2; 100%). Meta-analysis of 3105 (2258 intervention, 847 control) patients treated for gonococcal disease demonstrated a relative risk of treatment failure in the random-effects model of 0.33 (95% CI 0.20-0.55; I2 = 7%), favouring probenecid.
CONCLUSIONS
Probenecid-boosted β-lactam therapy is associated with improved outcomes in gonococcal disease. Pharmacokinetic data suggest that probenecid-boosted oral β-lactam therapy may have a broader application, but appropriately powered mechanistic and efficacy studies are required.
Topics: Amoxicillin; Anti-Bacterial Agents; Gonorrhea; Humans; Monobactams; Probenecid; beta-Lactams
PubMed: 35726853
DOI: 10.1093/jac/dkac200 -
European Journal of Clinical... Sep 2023This study aimed to report reference method antimicrobial susceptibility results for 24,937 recent (2019-2021) clinical isolates of Enterobacterales from 27 countries in...
In vitro activity of aztreonam-avibactam against Enterobacterales isolates collected in Latin America, Africa/Middle East, Asia, and Eurasia for the ATLAS Global Surveillance Program in 2019-2021.
This study aimed to report reference method antimicrobial susceptibility results for 24,937 recent (2019-2021) clinical isolates of Enterobacterales from 27 countries in Latin America, Eurasia, Africa/Middle East, and Asia with a focus on the investigational combination aztreonam-avibactam against metallo-β-lactamase (MBL) isolates. Antimicrobial susceptibility testing was performed by the CLSI broth microdilution methodology. Minimum inhibitory concentrations (MICs) were interpreted using the CLSI (2022) breakpoints for all agents except aztreonam-avibactam (provisional pharmacokinetic/pharmacodynamic susceptible breakpoint, ≤ 8 mg/L) and tigecycline (US-FDA). Molecular testing for β-lactamase genes was performed on isolates with meropenem MICs ≥ 2 mg/L, ceftazidime-avibactam MICs ≥ 16 mg/L, and/or aztreonam-avibactam MICs ≥ 16 mg/L, and 50% of isolates of Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Klebsiella variicola, and Proteus mirabilis testing with ceftazidime and/or aztreonam MICs ≥ 2 mg/L. Aztreonam-avibactam inhibited 99.8% of all Enterobacterales at ≤ 8 mg/L (MIC, 0.25 mg/L) and maintained activity against phenotypically resistant subsets of multidrug-resistant (MDR) (99.5% susceptible), extensively drug-resistant (XDR) (98.7%), and carbapenem-resistant Enterobacterales (CRE) (99.1%) isolates. At ≤ 8 mg/L, aztreonam-avibactam inhibited 100%, 99.6%, 99.6%, and 98.8% of KPC-, OXA-48-like-, ESBL-, and MBL-carrying isolates, respectively. MBL-positive isolates were most prevalent in India (20.5%), Guatemala (13.8%), and Jordan (13.2%). No differences in the activity of aztreonam-avibactam were observed across the global regions evaluated. At a concentration of ≤ 8 mg/L, aztreonam-avibactam inhibited almost all Enterobacterales collected from developing countries, including MBL-producing isolates. The widespread dissemination of MBLs among Enterobacterales highlights the unmet need for new agents such as aztreonam-avibactam for the treatment of CRE infections.
Topics: Humans; Aztreonam; Anti-Bacterial Agents; Latin America; Enterobacteriaceae; Ceftazidime; beta-Lactamases; Asia; Middle East; Carbapenems; Drug Combinations; Microbial Sensitivity Tests
PubMed: 37526796
DOI: 10.1007/s10096-023-04645-2 -
The Journal of Antimicrobial... Apr 2023To elucidate the role of a novel carbapenem-hydrolysing class D β-lactamase (RAD-1) from Riemerella anatipestifer.
OBJECTIVES
To elucidate the role of a novel carbapenem-hydrolysing class D β-lactamase (RAD-1) from Riemerella anatipestifer.
METHODS
We applied WGS and bioinformatic analysis to screen putative β-lactamase genes in R. anatipestifer SCVM0004. A putative class D β-lactamase gene was cloned into pET24a and transferred into Escherichia coli BL21 (DE3) for antibiotic susceptibility determination and protein purification. Meanwhile, the purified native protein was used to determine the enzymatic activities.
RESULTS
A class D β-lactamase, RAD-1, was identified in the genome of R. anatipestifer SCVM0004. It was distinct from all characterized class D β-lactamases (≤42% amino acid sequence identity). Searching in GenBank showed that blaRAD-1 was widely disseminated among R. anatipestifer. Genomic environment analysis indicated that the chromosomal structures of blaRAD-1-located regions were relatively conserved. Expression of RAD-1 in E. coli results in elevated MICs for various β-lactam antibiotics, including penicillins, extended-spectrum cephalosporins, a monobactam and carbapenems. Moreover, kinetic analysis of purified RAD-1 revealed: (i) high-level activity against penicillins; (ii) highest affinity for carbapenems; (iii) moderate hydrolysis of extended-spectrum cephalosporins and a monobactam; and (iv) no activity for oxacillin and cefoxitin.
CONCLUSIONS
This study identified a novel chromosomally located class D carbapenemase RAD-1 (Bush-Jacoby functional group 2def) in R. anatipestifer SCVM0004. Moreover, bioinformatic analysis confirmed that the RAD-1 was widely prevalent and conserved in R. anatipestifer.
Topics: Carbapenems; Escherichia coli; Kinetics; beta-Lactamases; Cephalosporins; Monobactams; Penicillins
PubMed: 36883515
DOI: 10.1093/jac/dkad058 -
Antimicrobial Agents and Chemotherapy Nov 2021Carbapenemase-producing pose an increasing medical threat. Combination therapy is often used for severe infections; however, there is little evidence supporting the...
Carbapenemase-producing pose an increasing medical threat. Combination therapy is often used for severe infections; however, there is little evidence supporting the optimal selection of drugs. This study aimed to determine the effects of polymyxin B combinations against carbapenemase-producing Escherichia coli. The interactions of polymyxin B in combination with aztreonam, meropenem, minocycline or rifampin against 20 clinical isolates of NDM and OXA-48-group-producing E. coli were evaluated using time-lapse microscopy; 24-h samples were spotted on plates with and without 4× MIC polymyxin B for viable counts. Whole-genome sequencing was applied to identify resistance genes and mutations. Finally, potential associations between combination effects and bacterial genotypes were assessed using Fisher's exact test. Synergistic and bactericidal effects were observed with polymyxin B and minocycline against 11/20 strains and with polymyxin B and rifampin against 9/20 strains. The combinations of polymyxin B and aztreonam or meropenem showed synergy against 2/20 strains. Negligible resistance development against polymyxin B was detected. Synergy with polymyxin B and minocycline was associated with genes involved in efflux (presence of , wild-type , and the mutation H44Q) and lipopolysaccharide synthesis ( C27Y, mutations, and L323S). Synergy with polymyxin B and rifampin was associated with sequence variations in , which plays a role in lipid A modification. Polymyxin B in combination with minocycline or rifampin frequently showed positive interactions against NDM- and OXA-48-group-producing E. coli. Synergy was associated with genes encoding efflux and components of the bacterial outer membrane.
Topics: Aztreonam; Bacterial Proteins; Escherichia coli; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests; Minocycline; Polymyxin B; Rifampin; beta-Lactamases
PubMed: 34516251
DOI: 10.1128/AAC.01065-21 -
Microbes and Infection 2023Klebsiella pneumoniae is an opportunistic pathogen, which frequently causes bacteremia. Ceftazidime and meropenem, two important beta-lactam antibiotics for treatment of...
Klebsiella pneumoniae is an opportunistic pathogen, which frequently causes bacteremia. Ceftazidime and meropenem, two important beta-lactam antibiotics for treatment of K. pneumoniae infections, induce morphological changes in bacteria when examined in vitro. Thirty clinical Klebsiella spp. Bacteremia isolates were analyzed for antimicrobial resistance and serum resistance. To determine whether complement influenced the resistance to ceftazidime of extended-spectrum beta-lactamase producing-isolates and sensitivity to meropenem, one serum resistant and one partly serum sensitive isolate were analyzed in normal human serum, heat-inactivated human serum, and growth medium with addition of beta-lactam antibiotics. HA391 was resistant to ceftazidime and had identical minimum inhibitory concentrations for meropenem in normal human serum, heat-inactivated serum and RPMI. In normal human serum, HA233 was inhibited by ceftazidime and had lower inhibitory concentrations of meropenem. Morphological changes induced by serum and beta-lactam antibiotics were analyzed by light- and electron microscopy. Light microscopy showed elongation of bacteria treated with ceftazidime. By electron microscopy membrane attack complexes were observed for HA233 in normal human serum, thereby facilitating beta-lactam antibiotics access to the periplasmic space and the peptidoglycan layer, explaining the increased killing of HA233 by beta-lactam antibiotics. Complement did not enhance beta-lactam killing of HA391, underlining the importance of serum susceptibility.
Topics: Humans; Anti-Bacterial Agents; Ceftazidime; Meropenem; Klebsiella pneumoniae; Monobactams; beta-Lactamases; Bacteremia; Microbial Sensitivity Tests; Klebsiella Infections
PubMed: 35944888
DOI: 10.1016/j.micinf.2022.105036 -
Antimicrobial Agents and Chemotherapy Oct 2022The wide spread of metallo-β-lactamase (MBL)-expressing bacteria has greatly threatened human health, and there is an urgent need for inhibitors against MBLs. Herein,...
The wide spread of metallo-β-lactamase (MBL)-expressing bacteria has greatly threatened human health, and there is an urgent need for inhibitors against MBLs. Herein, we present a cephalosporin-tripodalamine conjugate (DPASC) as a potent MBL inhibitor with a block-release design. The cephalosporin tag blocks the ligand binding site to reduce toxicity and is cleaved by MBLs to release active ligands to inhibit MBLs . The screening of MBL-expressing pathogenic strains with 16 μg/mL DPASC showed a decrease of the minimum inhibitory concentration of meropenem (MEM) by 16 to 512-fold, and its toxicity was minimal to human HepG2 cells, with an IC exceeding 512 μg/mL. An infection model with Galleria mellonella larvae showed an increased 3-day survival rate of 87% with the coadministration of DPASC and MEM, compared to 50% with MEM alone and no toxicity at a dose of 256 mg/kg of DPASC. Our findings with DPASC demonstrate that it is an effective MBL inhibitor and that the block-release strategy could be useful for the development of new MBL inhibitors.
Topics: Humans; beta-Lactamases; Meropenem; Cephalosporins; Ligands; Anti-Bacterial Agents; beta-Lactamase Inhibitors; Microbial Sensitivity Tests; Monobactams
PubMed: 36094199
DOI: 10.1128/aac.00352-22 -
Frontiers in Cellular and Infection... 2021To assess the efficacy of aztreonam-avibactam-auranofin (ATM-AVI-AUR) against a collection of 88 carbapenemase-producing (CPE) clinical isolates and 6 selected...
OBJECTIVES
To assess the efficacy of aztreonam-avibactam-auranofin (ATM-AVI-AUR) against a collection of 88 carbapenemase-producing (CPE) clinical isolates and 6 selected ATM-AVI-resistant CPE with CMY-16 Tyr150Ser and Asn346His mutants or transformants.
METHODS
MICs of imipenem, ceftazidime-avibact8am (CAZ-AVI), ATM-AVI, CAZ-AVI-AUR and ATM-AVI-AUR were determined the broth microdilution method. Genetic background and carbapenemase genes were determined by PCR and Sanger sequencing.
RESULTS
AUR alone showed little antibacterial activity with AUR MICs were greater than 64 μg/mL for all the 88 clinical CPE isolates. The addition of AUR (16 μg/mL) resulted in an 3-folding dilutions MIC reduction of ATM-AVI MIC (0.5 to 0.0625 μg/mL) and a 2-folding dilutions MIC reduction of MIC (1 to 0.25 μg/mL) against all 88 clinical CPE isolates, respectively. Notably, the reduced ATM-AVI MIC values were mainly found in MBL-producers, and the MIC and MIC reduced by 2-folding dilutions (0.25 to 0.0625 μg/mL) and 3-folding dilutions (2 to 0.25 μg/mL) respectively by AUR among the 51 MBL-producers. By contrast, the addition of AUR did not showed significant effects on ATM-AVI MIC (0.0625 μg/mL) and MIC (0.125 μg/mL) among single KPC-producers. Interestingly, the addition of AUR restored the ATM-AVI susceptibility against the 6 selected ATM-AVI-resistant CMY-16 Tyr150Ser and Asn346His mutants or transfromants, with the MICs reduced from ≥32 μg/mL (32->256 μg/mL) to ≤8 μg/mL (0.0625-8 μg/mL).
CONCLUSIONS
Our results demonstrated that AUR potentiated the activities of CAZ-AVI and ATM-AVI against MBL-producing isolates . Importantly, AUR restored the ATM-AVI activity against ATM-AVI resistant mutant strains. As a clinically approved drug, AUR might be repurposed in combination with ATM-AVI to treat infections caused by highly resistant MBL-producing
Topics: Auranofin; Azabicyclo Compounds; Aztreonam; beta-Lactamases
PubMed: 34778107
DOI: 10.3389/fcimb.2021.755763 -
Annals of Clinical Microbiology and... May 2023Bloodstream infection (BSI) caused by Carbapenem-Resistant Enterobacteriaceae (CRE) are associated with poor outcomes in hematological patients. The aim of this study...
PURPOSE
Bloodstream infection (BSI) caused by Carbapenem-Resistant Enterobacteriaceae (CRE) are associated with poor outcomes in hematological patients. The aim of this study was to identify risk factors for mortality and evaluate the value of epidemiological feature of carbapenemases in guiding antimicrobial treatment options.
METHODS
Hematological patients with monomicrobial CRE BSI between January 2012 and April 2021 were included. The primary outcome was all-cause mortality 30 days after BSI onset.
RESULTS
A total of 94 patients were documented in the study period. Escherichia coli was the most common Enterobacteriaceae, followed by Klebsiella pneumoniae. 66 CRE strains were tested for carbapenemase genes, and 81.8% (54/66) were positive, including NDM (36/54), KPC (16/54), IMP (1/54). Besides, one E. coli isolate was found to express both NDM and OXA-48-like genes. Overall, 28 patients received an antimicrobial treatment containing ceftazidime-avibactam (CAZ-AVI), of which 21 cases were combined with aztreonam. The remaining 66 patients were treated with other active antibiotics (OAAs). The 30-day mortality rate was 28.7% (27/94) for all patients, and was only 7.1% ((2/28) for patients treated with CAZ-AVI. In multivariate analysis, the presence of septic shock at BSI onset (OR 10.526, 95% CI 1.376-76.923) and pulmonary infection (OR 6.289, 95% CI 1.351-29.412) were independently risk factors for 30-day mortality. Comparing different antimicrobial regimens, CAZ-AVI showed a significant survive benefit than OAAs (OR 0.068, 95% CI 0.007-0.651).
CONCLUSION
CAZ-AVI-containing regimen is superior to OAAs for CRE BSI. As the predominance of blaNDM in our center, we recommend the combination with aztreonam when choose CAZ-AVI.
Topics: Humans; Carbapenem-Resistant Enterobacteriaceae; Aztreonam; Escherichia coli; Ceftazidime; Anti-Bacterial Agents; Klebsiella pneumoniae; Enterobacteriaceae Infections; Drug Combinations; Sepsis; Risk Factors; Microbial Sensitivity Tests
PubMed: 37202758
DOI: 10.1186/s12941-023-00586-y -
Pragmatic options for dose optimization of ceftazidime/avibactam with aztreonam in complex patients.The Journal of Antimicrobial... Mar 2021Avibactam is a β-lactamase inhibitor that is combined with aztreonam against Enterobacterales co-expressing serine- and metallo-β-lactamases (MBL). Optimal dosing of... (Observational Study)
Observational Study
BACKGROUND
Avibactam is a β-lactamase inhibitor that is combined with aztreonam against Enterobacterales co-expressing serine- and metallo-β-lactamases (MBL). Optimal dosing of aztreonam with avibactam is not well-defined in critically ill patients and contingent on ceftazidime/avibactam product labelling.
OBJECTIVES
To identify a pragmatic dosing strategy for aztreonam with avibactam to maximize the probability of target attainment (PTA).
METHODS
We conducted a prospective observational pharmacokinetic study. Five blood samples were collected around the fourth dose of aztreonam or ceftazidime/avibactam and assayed for all three drugs. Population pharmacokinetic (PK) analysis coupled with Monte Carlo simulations were used to create a dosing nomogram for aztreonam and ceftazidime/avibactam based on drug-specific pharmacodynamic (PD) targets.
RESULTS
A total of 41 participants (59% male) median age of 75 years (IQR 63-79 years) were enrolled. They were critically ill (46%) with multiple comorbidities and complications including burns (20%). Population PK analysis identified higher volume of distribution and lower clearance (CL) compared with typical value expectations for aztreonam and ceftazidime/avibactam. Estimated glomerular filtration (eGFR) rate using the CKD-EPI equation predicted CL for all three drugs. The need for high doses of aztreonam and ceftazidime/avibactam above those in the existing product labels are not predicted by this analysis with the exception of ceftazidime/avibactam for patients with eGFR of 6-15 mL/min, in whom suboptimal PTA of ≤71% is predicted.
CONCLUSIONS
Pragmatic and lower daily-dose options are predicted for aztreonam and ceftazidime/avibactam when the eGFR is <90 mL/min. These options should be tested prospectively.
Topics: Aged; Anti-Bacterial Agents; Azabicyclo Compounds; Aztreonam; Ceftazidime; Drug Combinations; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; beta-Lactamases
PubMed: 33378458
DOI: 10.1093/jac/dkaa549